ABSTRACT Glomerulonephritis (GN) is a leading cause of morbidity and mortality associated with immune-mediated diseases, such as systemic lupus erythematosus (SLE). A hallmark of lupus GN is the appearance of auto- reactive antibodies against nucleic acids which form, together with complement factors, characteristic immune complex (IC) deposits in kidney glomeruli. These IC are thought to promote disease by two major mechanisms, i.e. by activation of immune cells via nucleic-acid recognizing Toll-like receptors (TLRs) and by complement- mediated cytotoxicity. Despite the coherence of this concept, therapeutic progress for this debilitating disease has been modest, and data shown in this proposal suggest an important pathogenic contribution of innate immune cells, specifically so-called ?patrolling monocytes? (PMo). Important advances were made over the last years with respect to the identification of genetic risk factors for SLE. We had identified one of these genetic risk factors, i.e. TNIP1/ABIN1, independently as TLR signaling molecule with selective, negative regulatory function for C/EBP?. This transcription factor controls various aspects of cell differentiation, including development of mentioned PMo, a cell type with emerging function in intravascular inflammation. Based on TNIP1?s trait as human SLE risk factor, our lab established Tnip1-/- mice, which we found to share major characteristics with human SLE, including autoimmunity and severe mesangial- proliferative GN with IC deposits (PNAS, 2011, Zhou et al). In preliminary data we show that GN in Tnip1-/- mice is driven by TLRs, consistent with the current model. Unexpectedly, however, we also found that GN proceeds independent of IC, but is mediated by innate immune cells. We identified the critical cell type as mentioned PMo, which accumulate at high numbers in kidney glomeruli. Strikingly, genetic deletion of PMo prevents kidney damage. As such, we identified a hitherto largely unsuspected cell type, i.e. PMo, as culprit that mediates GN in Tnip1-/- mice. Based on additional evidence, including mentioned function of C/EBP? in PMo development and, importantly, data demonstrating the presence of PMo in glomeruli of SLE patients, we hypothesize that TLR-driven deregulation of PMo biology via ABIN1 and C/EBP? represents a novel key pathogenicity axis in lupus and, possibly, other forms of GN. In this project, we will (i) characterize the key steps of deregulated PMo biology, i.e. cell differentiation and glomerular retention, (ii) define the molecular mechanism that is used by ABIN1 to control C/EBP?, (iii) establish a causal link between the C/EBP? pathway and GN and (iv) identify PMo-specific drug targets and test current and novel, more selective treatment options for their impact on PMo biology and lupus nephritis. Collectively, this project will characterize PMo biology as largely undefined mechanism in lupus GN from both mechanistic and therapeutic perspectives. Given the conceptual novelty of PMo-mediated end-organ damage in SLE, we expect that data obtained here will open new areas for therapeutic intervention.